PRINCIPLES OF TOXICOLOGY

16.2 BASIC PRINCIPLES 373
Once absorbed, solvents may be transported to other areas of the body by the blood, to organs
where biotransformation may occur, resulting in the formation of metabolites that can be excreted.
Significant differences exist between the uptake and potential for adverse effects from solvents,
based on the route of exposure. Absorption following ingestion or dermal exposure results in
absorption into the venous circulation, from which materials are rapidly transported to the liver
where they may be metabolized. Following inhalation exposure, however, much of the absorbed
chemical is introduced into the arterial circulation via the alveoli. This means that the absorbed
solvent may be distributed widely in the body prior to reaching the liver for metabolism,
degradation, and subsequent excretion.
Since solvents constitute a heterogeneous group of chemicals, there are many potential
metabolic breakdown pathways. However, in many instances there is involvement of the P450
enzyme system and the glutathione pathways, which catalyze oxidative reactions and conjugation
reactions to form substances that are water-soluble and can be excreted in the urine and, perhaps,
the bile. Several pathways may exist for the biotransformation of a specific solvent and some of
the excreted metabolites form the basis for biological monitoring programs that can be used to
characterize exposure (e.g., phenols from benzene metabolism, trichloroacetic acid obtained from
trichloroethene, and mandelic acid from styrene). These metabolic processes are discussed in
greater detail in Chapter 3.
Although it is well recognized that the metabolism of most solvents occurs primarily in the liver,
other organs also exhibit significant capacity for biotransformation (e.g., kidney, lung). Some organs
may be capable of only some of the steps in the process, potentially leading to accumulation of toxic
metabolites if the first steps of the biotransformation pathway are present, but not the subsequent steps.
For example, whereas an aldehyde metabolite may be metabolized readily in the liver, the same
aldehyde may accumulate in the lung and cause pulmonary damage due to a lack of aldehyde
dehydrogenase enzyme in that organ. In addition to the generally beneficial aspects of biotransformation
and excretion, metabolism may generate products that are more toxic than the parent compound.
This process is termed metabolic activation or bioactivation, and the resultant reactive metabolic
intermediates (e.g., epoxides and radicals) are considered to be responsible for many of the toxic effects
of solvents, especially those of chronic character (see Chapter 3).
Enzymes that are critical to the metabolic processes may be increased in activity, or “induced,” by
various types of previous or concomitant exposures to chemicals, such as those from therapeutic drugs,
foods, alcohol, cigarette smoke, and other industrial exposures, including other solvents. Competitive
interactions between solvents in industrial contexts also may influence the toxic potential, complicating
the question of whether exposure to multiple chemicals always should be considered to be worse than
individual exposures. A well-described example of interactive effects relates to methanol and ethanol,
both of which are substrates that compete for the alcohol dehydrogenase pathway. This observation of
biochemical competition led to the use of ethanol as an early treatment for acute methanol intoxication.
As another example, induction of the enzyme that is active in the biotransformation of trichloroethene
(TCE), as a result of chronic ethanol consumption, may influence sensitivity to the adverse effects of
TCE. Interactions between alcohols (e.g., ethanol, 2-propanol) and other solvents (e.g., carbon
tetrachloride, trichloroethene) have been described.
Saturation of the typical metabolic pathways that are responsible for biological breakdown may
cause a qualitative shift in metabolism to different pathways. Whereas the normal pathway may be one
of detoxification, saturation of that pathway may result in “shunting” to another pathway, resulting in
bioactivation. Examples in which this phenomenon has been demonstrated include 1,1,1-trichloroethane,
n-hexane, tetrachloroethene, and 1,1-dichloroethene.
In addition to the process of biotransformation and subsequent urinary excretion described above,
many solvents may be eliminated in changed or unchanged form by exhalation, an action that varies
with workload. This observation forms the basis for the practice of sampling expired air as a measure
of possible occupational exposure in some industrial medical surveillance programs.